Evidence will be sought for the site(s) and mechanism(s) of action of indole- and phenethylamine-type hallucinogenic drugs. Previous work has suggested several operant behaviors in rats that can serve as animal models for characterizing hallucinogenic activity. The basis of these behavioral disruptions appears to relate to a decreased rate of discharge of serotonergic (5-HT) neurons in the raphe nuclei, although altered activity in central catecholaminergic (CA) neurons may also occur. Electrically- or chemically-induced brain lesions of 5-HT or CA neurons will be placed in trained rats to determine effects on operant behavior. Subjects whose behavior is not affected or recovers after the lesions will be tested for effects of d-lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methamphetamine (DOM). Sham-lesioned subjects will be treated in the same manner to serve as controls. Many of these rats will be sacrificed at appropriate times for regional analysis of brain monoamines and metabolites; the remaining subjects will be studied for tolerance development to repeated daily doses of the drugs. In other animals trained to the operant task but unlesioned, the influence of pretreating with alpha-methyltyrosine, p-chlorophenylalanine, haloperidol, or cinanserin on the hallucinogenic drug effect will be determined. In cases in which the pretreatment alters the hallucinogenic activity, identically-treated rats will be sacrificed for analysis of brain monoamines and their major metabolites. The results should expand our understanding of the biochemical and psychological bases of hallucinogenic drug action and perhaps also yield clues to mechanisms of non-drug related psychopathology.